The broad goals of the research proposed in this renewal application are: 1) an increased understanding of chemical synaptic transmission in normal nervous systems as well as in certain neurological disorders, and 2) the development of pharmacological agents of potential therapeutic value in the treatment of neural dysfunction. In order to fulfill these goals, we have developed an interdisciplinary research effort involving studies of several neurotransmitter systems using the approaches of biochemistry, immunochemistry, immunocytochemistry, physiology, and pharmacology. Biochemical and immunochemical investigations will emphasize purification, characterization and antibody production for: 1) neurotransmitter-synthesizing enzymes (ChAT and GAD); 2) neurotransmitter receptors (ACh, nicotinic and muscarinic; GABA); and 3) neurotransmitter degradative enzymes (AChE and GABA-T). Furthermore, these studies will stress the improvement of methods for localizing molecules in morphological preparations of both vertebrate and invertebrate nervous systems. Immunocytochemical studies will focus upon the light and electron microscopic localization of molecules involved in neurotransmission and will emphasize the synaptic relationships formed by neurons which are identified by their constituent macromolecules. These morphological studies will be carried out in normal nervous systems and in those which have been experimentally altered to produce epilepsy or post-lesion plastic changes in neuronal circuitry. Physiological studies will focus upon fundamental ionic processes involved in synaptic transmission, neuronal excitability and repetitive action potentials. Model systems for mammalian, crayfish and Drosophila nervous systems will be investigated and the Drosophila material will include neurological mutants which exhibit defects that seem to resemble those observed in certain human neurological disorders. Pharmacological studies primarily will be concerned with the development and testing of therapeutic agents to modify GABAergic neurotransmitter systems. This work will utilize biochemical fractions of mouse brain, isolated crayfish stretch receptor neurons, in vitro mammalian nervous system preparations and isolated cerebral blood vessels.